GABAergic mechanisms of adolescent and emerging adult vulnerability to alcohol

描述(由申请人提供)： 退伍军人及其家人因酗酒造成的医疗和社会后果负担过重，因为退伍军人中酗酒的流行率是普通人群的3倍以上。虽然退伍军人酗酒增加的原因尚不清楚，但越来越多的证据表明，青春期或成年初期饮酒导致的大脑变化与成年后酗酒的发展之间存在联系。在青春期/成年初期大量饮酒可能会扰乱脆弱的大脑回路的成熟，并在认知、行为和对酒精的敏感性方面产生长期的变化。由于18岁至25岁的军人比平民更频繁、剂量更高，退伍军人更有可能在大脑对酒精暴露的长期后果特别敏感的时候大量饮酒。酒精领域的最新进展使人们对青少年和新兴成人大脑独特的酒精敏感性的神经机制有了深入的了解。特别是，突触外GABAA受体(EGABAARs)已被确定为重要的乙醇靶标。这些发育调节的GABA受体控制神经元和大脑回路的兴奋性，调节焦虑、学习、睡眠和饮酒。最近的证据表明，两种突触外GABA受体亚型，�4��和�5�？，调节海马区和杏仁核的神经元兴奋性和酒精敏感性。最近发表的研究表明，青春期暴饮式酒精暴露导致eGABAR介导的紧张性抑制的乙醇敏感性发生长期变化，这些变化可能涉及�4��和�5�？伽巴尔。有两种机制控制乙醇对eGABAAR介导的紧张性抑制的敏感性：表达的GABAAR亚型和环境中的GABA浓度。这些机制之间的关键相互作用可能是青春期和成年初期神经元和大脑回路对酒精敏感性的发育变化的基础。该项目的目的将(1)使用体外脑片的靶向蛋白质组学和电生理学，以彻底表征eGABAAR亚型的表达和环境中的GABA在控制齿状回和杏仁核的紧张性抑制中的作用；(2)拮抗乙醇对�4��GABAAR的影响，以确定它们是否在产生暴饮式酒精暴露的长期效应中发挥关键作用；以及(3)在体内药理学操作eGABAAR，以证明eGABAAR介导的紧张性抑制的变化与乙醇诱导的认知和自我给药变化之间的关键联系。调节eGABAARs的药物目前已经上市，更多的药物正在开发中；因此，这些关于紧张性抑制在产生乙醇的神经效应中的作用的研究可能在短期内具有翻译价值。这些研究的结果可能会导致确定酒精滥用的新治疗方法。

DESCRIPTION (provided by applicant): Veterans and their families are disproportionately burdened by the medical and social consequences of alcohol abuse because the prevalence of alcoholism in veterans is over 3 times that of the general population. While the cause of increased alcohol abuse by veterans is not known, a growing body of evidence suggests a link between brain changes caused by alcohol drinking during adolescence or emerging adulthood and the later development of alcohol abuse in adults. Heavy drinking during adolescence / emerging adulthood may disrupt the maturation of vulnerable brain circuits and produce long-term changes in cognition, behavior, and sensitivity to ethanol. Because military personnel ages 18-25 use alcohol more frequently and at higher doses than civilians, veterans are more likely to have engaged in heavy drinking at a time when the brain may be particularly sensitive to the long-lasting consequences of ethanol exposure. Recent advances in the alcohol field are producing insights into the neurological mechanisms that underlie the unique ethanol sensitivity of the adolescent and emerging adult brain. In particular, extrasynaptic GABAA receptors (eGABAARs) have been identified as important ethanol targets. These developmentally regulated GABAARs control the excitability of neurons and brain circuits and modulate anxiety, learning, sleep, and ethanol drinking. Recent evidence suggests that 2 extrasynaptic GABAAR subtypes, �4�� and �5�?, regulate neuron excitability and ethanol sensitivity in the hippocampus and amygdala. Recently published studies have shown that binge-pattern ethanol exposure during adolescence produces long-term changes in the ethanol sensitivity of eGABAAR-mediated tonic inhibition, and these changes may involve �4�� and �5�? GABAARs. Two mechanisms control the ethanol sensitivity of eGABAAR-mediated tonic inhibition: the GABAAR subtype expressed and the ambient GABA concentration. Critical interactions between these mechanisms may underlie developmental changes in the ethanol sensitivity of neurons and brain circuits during adolescence and emerging adulthood. The aims of this project will (1) use targeted proteomics and electrophysiology in ex vivo brain slices to thoroughly characterize the roles of eGABAAR subtype expression and ambient GABA in controlling tonic inhibition in the dentate gyrus and amygdala; (2) antagonize the effects of ethanol on �4�� GABAARs to determine if they play an essential role in producing the long-term effects of binge-pattern ethanol exposure; and (3) pharmacologically manipulate eGABAARs in vivo to demonstrate a critical link between changes in eGABAAR-mediated tonic inhibition and ethanol-induced changes in cognition and ethanol self- administration. Drugs that regulate eGABAARs are currently available, and more are in development; therefore, these studies of tonic inhibition's role in producing ethanol's neurological effects may have near-term translational value. The results of these studies could lead to the identification of new treatments for alcohol abuse.